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A Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia (STABILIZE-CKD)

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ClinicalTrials.gov Identifier: NCT05056727
Recruitment Status : Recruiting
First Posted : September 24, 2021
Last Update Posted : January 11, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE September 1, 2021
First Posted Date  ICMJE September 24, 2021
Last Update Posted Date January 11, 2023
Actual Study Start Date  ICMJE September 30, 2021
Estimated Primary Completion Date January 19, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 2, 2022)
Co-primary: Total eGFR slope and Chronic eGFR slope [ Time Frame: Co-primary: Total slope: from randomisation visit to the end of the maintenance phase at Week 104; Chronic slope: from Week 12 visit to the end of the maintenance phase at Week 104 ]
Both of the primary endpoints must be met in order for the study to be declared successful, i.e., co-primary endpoints
Original Primary Outcome Measures  ICMJE
 (submitted: September 14, 2021)
Total eGFR slope and Chronic eGFR slope [ Time Frame: Total slope: from randomisation visit to the end of the maintenance phase at Week 104; Chronic slope: from Week 12 visit to the end of the maintenance phase at Week 104 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2021)
  • Time from randomisation to the first occurrence of any component in the composite of: Sustained ≥ 40% decline in eGFR; Onset of ESKD (kidney transplantation, maintenance dialysis, or sustained low eGFR); Death from kidney failure [ Time Frame: From randomisation visit to the end of the maintenance phase at Week 104 ]
  • Time from randomisation to first lisinopril/valsartan dose decrease [ Time Frame: From randomisation visit to the end of the maintenance phase at Week 104 ]
  • UACR measurements [ Time Frame: From randomisation visit to the end of the maintenance phase at Week 104 ]
  • Serum bicarbonate measurements [ Time Frame: From randomisation visit to the end of the maintenance phase at Week 104 ]
  • S-K level classification [ Time Frame: From randomisation visit to the end of the maintenance phase at Week 104 ]
    Normal (3.5-5.0 mmol/L) or non-normal (< 3.5 or > 5.0 mmol/L)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 14, 2021)
AEs/SAEs [ Time Frame: From screening visit to follow-up visit at Week 105 ]
During screening only SAEs will be collected. Assessments related to AEs cover:
  • Occurrence/frequency
  • Relationship to study intervention as assessed by investigator
  • Intensity
  • Seriousness
  • Death
  • AEs leading to discontinuation of study intervention
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia
Official Title  ICMJE A Phase 3, International, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on CKD Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia
Brief Summary The purpose of this study is to evaluate the effect of Sodium Zirconium Cyclosilicate (SZC), as adjunct to ACEi/ARB therapy (lisinopril or valsartan), on slowing CKD progression (assessed as the reduction in participant's glomerular filtration rate [eGFR] decline over time) in participants with hyperkalaemia or at high risk of hyperkalaemia.
Detailed Description

This is a Phase 3, international, randomised withdrawal, double-blind, parallel-group, placebo-controlled study, to evaluate the effect of SZC as adjunct to RAASi therapy (lisinopril or valsartan) in slowing CKD progression in participants with CKD and hyperkalaemia or at risk of hyperkalaemia.

Specifically, the study will include participants with hyperkalaemia (S-K > 5.0 to ≤ 6.5 mmol/L by central laboratory) who are on adequate or limited RAASi therapy due to hyperkalaemia, and participants with normokalaemia (S-K ≥ 3.5 to ≤ 5.0 mmol/L by central laboratory) who are on limited RAASi therapy due to high risk of hyperkalaemia. High risk of hyperkalaemia is defined as (1) participants with a previous medical history or record of hyperkalaemia within the prior 24 months who are on limited RAASi therapy despite indication in CKD; (2) participants in whom RAASi therapy is indicated in CKD but are on limited RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L; and (3) participants in whom RAASi therapy has been discontinued or reduced to suboptimal doses because of hyperkalaemia.

A participant is expected to be in the study for approximately 28 months, which includes up to 13 days for the screening period, 27 months for the intervention period, and 1 week for follow-up. The 27-month intervention period of the study consists of 3 phases, an initiation phase (up to 72 hours), a run-in phase (3 months/up to Day 90), and a maintenance phase (24 months/104 weeks).

The initial dose of SZC will be administered to participants during the initiation phase. No changes will be made to the ACEi or ARB therapy at this stage. As soon as possible after the participant is confirmed to be normokalaemic at the end of the initiation phase, the participant will enter the run-in phase. Participants will receive open-label SZC and either lisinopril or valsartan. The aim of the run-in phase is to increase ACEi or ARB therapy stepwise to their maximum doses. After a 3-month run-in period for RAASi dose optimization while on SZC, participants will be randomized to SZC or placebo and followed during the subsequent 24 months of maintenance phase for efficacy and safety assessments.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Renal Insufficiency, Chronic
  • Hyperkalemia
Intervention  ICMJE
  • Drug: Sodium Zirconium Cyclosilicate (SZC)

    Powder for oral suspension in a sachet. Unit dose strength: 5 or 10 g SZC. Single dose will consist of 1-3 sachets.

    During Initiation Phase:

    • S-K > 5 to ≤ 6.5 mmol/L (measured by L-Lab): Single dose contains 10 g SZC that should be suspended in 45 mL of water. The 10 g SZC single dose should be administered three times daily for up to 72 hours until normokalaemic (S-K 3.5-5.0 mmol/L); the total daily dose is 30 g SZC.
    • S-K ≥ 3.5 to ≤ 5 mmol/L (measured by L-Lab): Single dose contains 5 g SZC that should be suspended in 45 mL of water and administered once daily for 48 hours.

    During Run-in and Maintenance Phases:

    - Single dose contains 5 g SZC administered every other day or 5, 10, or 15 g SZC administered once daily that should be suspended in 45 mL of water.

    Other Name: Lokelma TM
  • Drug: Placebo

    Powder for oral suspension in a sachet. Placebo to match 5 or 10 g. Single dose will consist of 1-3 sachets.

    During Maintenance Phase:

    - Single dose contains 5 g placebo administered every other day or 5, 10, or 15 g placebo administered once daily that should be suspended in 45 mL of water.

  • Drug: Lisinopril
    Tablet for oral administration. Unit dose strength: 2.5, 5, 10 or 20 mg. Dosage level: 5, 10, 20, or 40 mg administered once daily.
  • Drug: Valsartan
    Tablet or capsule for oral administration. Unit dose strength: 40, 80 or 160 mg. Dosage level: 40, 80, 160, or 320 mg administered once daily.
  • Drug: Irbesartan

    Tablet for oral administration. Unit dose strength: 75, 150 or 300 mg. Dosage level: 75, 150, or 300 mg administered once daily.

    The study is designed to use valsartan as the selected ARB therapy adjunct to SZC. However, if an actual shortage of valsartan in a local market jeopardises the ability of participants to enter or continue in the study, valsartan can be temporarily substituted with irbesartan until the shortage of valsartan is resolved.

Study Arms  ICMJE
  • Experimental: Sodium Zirconium Cyclosilicate (SZC)
    SZC 5 g every other day to 15 g once daily + Lisinopril/Valsartan
    Interventions:
    • Drug: Sodium Zirconium Cyclosilicate (SZC)
    • Drug: Lisinopril
    • Drug: Valsartan
    • Drug: Irbesartan
  • Placebo Comparator: Placebo
    Placebo + Lisinopril/Valsartan
    Interventions:
    • Drug: Placebo
    • Drug: Lisinopril
    • Drug: Valsartan
    • Drug: Irbesartan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 14, 2021)
1500
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 19, 2026
Estimated Primary Completion Date January 19, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and protocol
  • Must be ≥ 18 years of age at the time of signing the informed consent.
  • Must have eGFR ≥ 25 and ≤ 59 mL/min/1.73m2 as calculated by central laboratory (CKD-EPI formula) at screening (Visit 1)
  • Must have UACR ≥ 200 and ≤ 5000 mg/g as calculated by central laboratory at screening (Visit 1). If the first sample does not fulfil eligibility criteria, a second sample can be obtained during the screening period; if so, the UACR measurement from the second sample must be within the eligibility range.
  • Any of the following criteria, a or b, at screening (Visit 1):

    1. Cohort A: Hyperkalaemia (S-K > 5.0 to ≤ 6.5 mmol/L) as measured by the central laboratory, and on adequate* or limited** RAASi therapy due to hyperkalaemia.
    2. Cohort B: Normokalaemia (S-K ≥ 3.5 to ≤ 5.0 mmol/L) as measured by the central laboratory and on limited** RAASi therapy due to high risk of hyperkalaemia. High risk of hyperkalaemia is defined as:

    (i) Participants with a previous medical history or record of hyperkalaemia within the prior 24 months, who are on limited** RAASi therapy despite indication in CKD.

(ii) Participants in whom RAASi therapy is indicated in CKD, who are on limited** RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L.

(iii) Participants in whom RAASi therapy has been discontinued or reduced to suboptimal* doses because of hyperkalaemia.

*Adequate RAASi dose levels are defined in protocol; doses lower than these are considered as suboptimal.

**Limited RAASi therapy is defined as no or suboptimal RAASi therapy according to dosing guidance provided in protocol.

  • If on thiazide or loop diuretics, the dose must have been stable for 2 weeks prior to screening (Visit 1).
  • If on RAASi therapy, the dose must have been stable for one month prior to screening (Visit 1) and remain stable during screening.
  • If on an SGLT2i treatment (ie, dapagliflozin and canagliflozin), finerenone, or any other medications in these 2 classes that are approved for CKD, the dose must have been stable for 3 months prior to screening (Visit 1).
  • Participants must be one-year postmenopausal, surgically sterile, or using one highly effective form of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). They should have been stable on their chosen method of birth control for a minimum of one month prior to screening (Visit 1) and willing to remain on the birth control until one month after the last dose of study intervention.

Exclusion Criteria:

  • New York Heart Association class III to IV congestive heart failure at the time of screening (Visit 1) or previous history of severe or symptomatic heart failure.
  • Myocardial infarction, unstable angina, stroke, or transient ischaemic attack within 3 months prior to screening (Visit 1).
  • Participants with a known history of systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg within 2 weeks prior to screening (Visit 1) are excluded. In addition, any participant with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg as measured at screening (Visit 1) and confirmed by repeated measurement is excluded. Participants may be rescreened once blood pressure is controlled.
  • QTcF > 550 msec at screening (Visit 1).
  • History of QT prolongation associated with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome.
  • Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation and heart rate controlled by medication are permitted.
  • Lupus nephritis or anti-neutrophil cytoplasmic antibody-associated vasculitis.
  • Change in renal function requiring hospitalisation or dialysis within 3 months prior to screening (Visit 1).
  • History of renal transplant (or anticipated need for renal transplant during the study).
  • Severe hepatic impairment, biliary cirrhosis, or cholestasis.
  • History of hereditary or idiopathic angioedema.
  • Any prior hypersensitivity to ACEi or ARB that in the investigator's judgment precludes use of lisinopril and valsartan/irbesartan. Prior hypersensitivity reactions to consider include, but are not limited to, development of angioedema, icterus, hepatitis, or neutropaenia or thrombocytopaenia requiring treatment modification.
  • Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
  • Any condition outside the CV and renal disease area such as, but not limited to, malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgment.
  • Active malignancy requiring treatment at the time of screening (Visit 1), except for successfully treated basal cell or treated squamous cell carcinoma.
  • S-K > 6.5 or < 3.5 mmol/L by local laboratory within 1 day prior to the scheduled first dose of SZC in the initiation phase.
  • Evidence of COVID-19 infection within 2 weeks prior to screening (Visit 1).
  • Treated with dual blockade of RAAS (combined use of an ACEi and ARB) within 3 months prior to screening (Visit 1).
  • Treated with an angiotensin receptor neprilysin inhibitor (ARNI; sacubitril/valsartan [Entresto®]) within 3 months prior to screening (Visit 1).
  • Treated with an MRA not approved for CKD within 3 months prior to screening (Visit 1).
  • Treated with aliskiren-containing products with 3 months prior to screening (Visit 1).
  • Treated with SPS (eg, Kayexalate, Resonium), CPS (Resonium Calcium), patiromer (Veltassa®), or SZC (Lokelma®) within 7 days prior to screening (Visit 1).
  • Participation in another clinical study with an investigational product administered within one month prior to screening (Visit 1).
  • Not willing or not able to change to lisinopril or valsartan/irbesartan, the protocol-mandated RAASi study intervention. Note: For participants taking a fixed combination of an ACEi or ARB with another agent (eg, calcium blockers or diuretics) as SoC, the investigator must make a judgment that it will be safe and efficacious for such participants to change to the study ACEi or ARB and to the other drug as separate agents.
  • Previous dosing with SZC in the present study.
  • Currently pregnant (confirmed with positive pregnancy test at screening [Visit 1]) or breastfeeding.
  • Judgment by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements.
  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Argentina,   Brazil,   Bulgaria,   Canada,   China,   Italy,   Japan,   Malaysia,   Mexico,   Philippines,   Poland,   Puerto Rico,   Russian Federation,   Spain,   Taiwan,   Thailand,   Turkey,   Ukraine,   United States,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05056727
Other Study ID Numbers  ICMJE D9488C00001
2021-001911-96 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Glenn M. Chertow, MD, MPH Stanford University School of Medicine, Stanford, CA USA
PRS Account AstraZeneca
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP